Lytgobi

LYTGOBI is indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements [see Dosage and Administration (2.1) ] . This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). LYTGOBI is a kinase inhibitor indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. ( 1 , 2.1 ) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

Tablets: 4 mg, round, white, film-coated tablets debossed with “4MG” on one side, and “FBN” on the other side. 16 mg, round, white, film-coated tablets debossed with “16MG” on one side and “FBN” on the other side. Tablets: 4 mg and 16 mg ( 3 )

None. None ( 4 )

Ocular Toxicity: LYTGOBI can cause retinal pigment epithelial detachment (RPED). Perform a comprehensive ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every 2 months for the first 6 months, and every 3 months thereafter and urgently at any time for visual symptoms. ( 2.3 , 5.1 ) Hyperphosphatemia and Soft Tissue Mineralization: Increases in phosphate levels can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis and vascular calcification. Monitor for hyperphosphatemia and withhold, reduce the dose, or permanently discontinue based on duration and severity of hyperphosphatemia. ( 2.3 , 5.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 )

5.1 Ocular Toxicity Retinal Pigment Epithelial Detachment (RPED) LYTGOBI can cause RPED, which may cause symptoms such as blurred vision. Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1) ] where ophthalmologic monitoring did not routinely include optical coherence tomography (OCT), RPED occurred in 9% of patients. The median time to first onset of RPED was 40 days. RPED led to dose interruption of LYTGOBI in 1.3% of patients, dose reduction in 1.6% of patients, and permanent discontinuation in 0.3% of patients. Perform a comprehensive ophthalmological examination, including OCT of the macula, prior to initiation of therapy, every 2 months for the first 6 months, and every 3 months thereafter. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of LYTGOBI. Withhold or reduce the dose of LYTGOBI as recommended [see Dosage and Administration (2.3) ]. Dry Eye/Corneal Keratitis Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1) ] , dry eye occurred in 15% of patients. Treat patients with ocular demulcents as needed.

5.2 Hyperphosphatemia and Soft Tissue Mineralization LYTGOBI can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of LYTGOBI [see Clinical Pharmacology (12.2) ] . Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1) ] , hyperphosphatemia was reported in 88% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 5 days (range 3-117). Phosphate binders were received by 77% of patients who received LYTGOBI. Monitor for hyperphosphatemia throughout treatment. Initiate a low phosphate diet and phosphate lowering therapy when serum phosphate level is ≥5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate or intensify phosphate lowering therapy and dose reduce, withhold, or permanently discontinue LYTGOBI based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3) ] .

5.3 Embryo-Fetal Toxicity Based on findings in an animal study and its mechanism of action, LYTGOBI can cause fetal harm when administered to a pregnant woman. Oral administration of futibatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure at the clinical dose of 20 mg based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose of LYTGOBI. Advise males with female partners of reproductive potential to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

The following adverse reactions are discussed elsewhere in the labeling: Ocular Toxicity [see Warnings and Precautions (5.1) ] Hyperphosphatemia and Soft Tissue Mineralization [see Warnings and Precautions (5.2) ] Most common (≥20%) adverse reactions were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting. ( 6.1 ) Most common laboratory abnormalities (≥20%) were increased phosphate, increased creatinine, decreased hemoglobin, increased glucose, increased calcium, decreased sodium, decreased phosphate, increased alanine aminotransferase, increased alkaline phosphatase, decreased lymphocytes, increased aspartate aminotransferase, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, decreased glucose, increased prothrombin international normalized ratio, and decreased potassium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taiho Oncology Inc. at 1-844-878-2446 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LYTGOBI as a single agent at 20 mg orally once daily in 318 patients including 145 patients with cholangiocarcinoma and 173 patients with other advanced solid tumors. Among 318 patients who received LYTGOBI, 37% were exposed for 6 months or longer and 13% were exposed for greater than 12 months. Previously Treated, Unresectable Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma The safety of LYTGOBI was evaluated in Study TAS-120-101, which included 103 patients with previously treated, unresectable locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions or other gene rearrangements [see Clinical Studies (14.1) ] . Patients were treated with LYTGOBI 20 mg orally once daily until disease progression or unacceptable toxicity. The median duration of treatment was 9 months (range: 0.5 – 25 months). Serious adverse reactions occurred in 39% of patients receiving LYTGOBI. Serious adverse reactions in ≥2% of patients who received LYTGOBI included pyrexia (3.9%), gastrointestinal hemorrhage (3.9%), ascites (2.9%), musculoskeletal pain (2.9%), and bile duct obstruction (2.9%). Permanent discontinuation due to an adverse reaction occurred in 4.9% of patients who received LYTGOBI. Adverse reactions requiring permanent discontinuation of LYTGOBI in one patient each were esophagitis, oral dysesthesia, bile duct obstruction, dizziness, and anemia. Dosage interruptions due to an adverse reaction occurred in 66% of patients who received LYTGOBI. Adverse reactions requiring dosage interruption in ≥5% of patients included hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, increased alanine aminotransferase, increased aspartate aminotransferase, and fatigue. Dose reductions due to an adverse reaction occurred in 58% of patients who received LYTGOBI. Adverse reactions requiring dosage reductions in ≥2% of patients who received LYTGOBI included hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, fatigue, increased alanine aminotransferase, increased aspartate aminotransferase, nail toxicity, and stomatitis. The most common (≥20%) adverse reactions were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting. The most common laboratory abnormalities (≥20%) were increased phosphate, increased creatinine, decreased hemoglobin, increased glucose, increased calcium, decreased sodium, decreased phosphate, increased alanine aminotransferase, increased alkaline phosphatase, decreased lymphocyte, increased aspartate aminotransferase, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, decreased glucose, increased prothrombin international normalized ratio, and decreased potassium. Table 3 summarizes the adverse reactions in TAS-120-101. Table 4 summarizes laboratory abnormalities in TAS-120-101. Table 3: Adverse Reactions (≥15%) in Patients Receiving LYTGOBI in Study TAS-120-101 LYTGOBI N = 103 Adverse Reaction All Grades a (%) Grade 3 (%) a Graded per NCI CTCAE 4.03. b Includes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. c Includes diarrhea, colitis, and gastroenteritis. d Includes stomatitis, glossitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and tongue ulceration. e Includes abdominal pain, abdominal discomfort, abdominal pain upper, gastrointestinal pain, and hepatic pain. f Includes vomiting and hematemesis. g Includes fatigue and asthenia. h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. i Includes arthralgia and arthritis. j Includes dry eye, keratitis, lacrimation increased, photokeratitis, punctate keratitis, and ulcerative keratitis. k Includes dysgeusia, ageusia, and taste disorder. l Includes urinary tract infection, cystitis, and dysuria. Skin and subcutaneous tissue disorders Nail toxicity b 47

1.9 Alopecia 34 0 Dry skin 29 0 Palmar-plantar erythrodysesthesia syndrome 21

4.9 Gastrointestinal disorders Constipation 39 0 Diarrhea c 39 1 Dry mouth 35 0 Stomatitis d 30 6 Abdominal pain e 30

2.9 Nausea 24

1.9 Vomiting f 20 1 General disorders Fatigue g 37 8 Metabolism and nutrition disorders Decreased appetite 23

2.9 Musculoskeletal and connective tissue disorder Musculoskeletal pain h 43

3.9 Arthralgia i 25 0 Eye disorders Dry eye j 25 1 Nervous system disorders Dysgeusia k 25 0 Infections Urinary tract infection l 23

2.9 Investigations Weight decreased 18

3.9 Clinically relevant adverse reactions occurring in ≤15% of patients included retinal pigment epithelial detachment (RPED, 7.8%). Table 4: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving LYTGOBI in TAS-120-101 LYTGOBI N = 103 Laboratory Abnormality a All Grades b (%) Grades 3 or 4 (%) a Graded per NCI CTCAE 4.03. b Percentages are based on patients with data at both baseline and at least one post-baseline data value. c NCI CTCAE 4.03 does not define grades for increased phosphate. Laboratory value shift table categories were used to assess increased phosphorus levels (Grades ≥3 defined as >7 mg/dL). d Graded based on comparison to upper limit of normal. […]

Strong CYP3A inhibitors : Avoid concomitant use. ( 7.1 ) Strong CYP3A inducers : Avoid concomitant use. ( 7.1 )

7.1 Effect of Other Drugs on LYTGOBI Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors with LYTGOBI. Futibatinib is a CYP3A substrate [see Clinical Pharmacology (12.3) ] . Concomitant use of a strong CYP3A inhibitor increases futibatinib exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. Strong CYP3A Inducers Avoid concomitant use of strong CYP3A inducers with LYTGOBI. Futibatinib is a CYP3A substrate [see Clinical Pharmacology (12.3) ] . Concomitant use of a strong CYP3A inducer decreases futibatinib exposure [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of LYTGOBI.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings in an animal study and its mechanism of action, LYTGOBI can cause fetal harm or loss of pregnancy when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of LYTGOBI in pregnant women. Oral administration of futibatinib to pregnant rats during the period of organogenesis at maternal plasma exposures below the human exposure at the clinical dose of 20 mg resulted in fetal malformations, fetal growth retardation, and embryo-fetal death ( see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Once daily oral administration of futibatinib to pregnant rats during the period of organogenesis resulted in 100% embryofetal mortality due to post-implantation loss at doses ≥10 mg/kg (approximately 5 times the recommended clinical dose of 20 mg based on body surface area, BSA). Fetal survival was unaffected at 0.5 mg/kg per day; however, once daily oral administration of futibatinib at the 0.5 mg/kg dose level (approximately 0.2 times the recommended clinical dose of 20 mg based on BSA) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.

8.2 Lactation Risk Summary There are no data on the presence of futibatinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions from LYTGOBI in breastfed children, advise women not to breastfeed during treatment and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential LYTGOBI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating LYTGOBI [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose. Males Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose.

8.4 Pediatric Use The safety and effectiveness of LYTGOBI have not been established in pediatric patients. Animal Toxicity Data In 4- or 13-week repeat-dose toxicology studies in adult rats and dogs, findings included increased inorganic phosphorus and calcium in plasma, ectopic mineralization in various organs and tissues, and lesions in bone/cartilage at futibatinib exposures lower than the human exposure at the clinical dose of 20 mg. Findings in rats also included corneal lesions. Evidence of recovery in rats and dogs was observed four weeks after cessation of dosing except for the ectopic mineralization.

8.5 Geriatric Use Of the 103 patients treated with LYTGOBI in Study TAS-120-101, 22% were 65 years or older. Based on available data, no overall differences in safety or effectiveness of LYTGOBI have been observed between patients 65 years of age and older and younger adult patients.

8.7 Hepatic Impairment There are limited data in patients treated with LYTGOBI with total bilirubin >1.5🞨 ULN, and patients with cholangiocarcinoma with total bilirubin >3🞨 ULN were excluded from enrollment in clinical trials. Patients with cirrhosis and total bilirubin >1.5🞨 ULN to 3🞨 ULN may have the potential for increased adverse reactions compared to patients with normal hepatic function due to higher unbound futibatinib exposure [see Clinical Pharmacology (12.3) ] .

Futibatinib is a small molecule kinase inhibitor of FGFR 1, 2, 3, and 4 with IC 50 values of less than 4 nM. Futibatinib covalently binds FGFR. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Futibatinib inhibited FGFR phosphorylation and downstream signaling and decreased cell viability in cancer cell lines with FGFR alterations including FGFR fusions/rearrangements, amplifications, and mutations. Futibatinib demonstrated anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR genetic alterations.